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A high mutational burden is not fully responsible for ageing

Despite previous thoughts, researchers have now found that cells tolerate a lot more mutations without impacting their function.

Mutational burden

Replication of the genome is a key step during each cell division. The body ensures there are low rates of error through a variety of mechanisms, including the fidelity of base incorporation, proofreading capabilities of polymerases and DNA mismatch repair machinery. Researchers have previously identified mutations within nuclear polymerases in some human cancers. The defective proofreading in these cases results in a high burden of somatic mutations with distinctive mutational signatures.

One of the primary biological mechanisms underlying ageing is the accumulation of somatic mutations. This hypothesis is based off the fact that mutations accumulate throughout life and a higher mutational load results in widespread malfunction of cell biology. While recent reports have supported the fact that somatic mutational burden in normal cells does increase during life, whether or not this accumulation has significant biological consequences remains unclear.  

The wider biological consequences

In a recent study, published in Nature Genetics, researchers applied cutting-edge techniques to sequence the DNA of normal cells and tissues from patients who have inherited faulty copies of the DNA polymerase genes, POLE and POLD1.  

By comparing tissue samples, the team found that normal tissues from those carrying mutated DNA polymerases had elevated mutational rates. However, these individuals did not show features of early onset ageing or age-related diseases. This is despite the fact that their ‘mutational age’ would have made them hundreds of years old. Although there is an increased cancer risk for these individuals, this study demonstrates that germline POLE/POLD1 mutations do not result in features associated with premature ageing.

Overall, these findings suggest that the build-up of mutations in normal cells is unlikely to be the only factor in the development of ageing-related diseases. They have also added to the ongoing debate surrounding the causes of ageing, indicating that there is a need to further understand the biological processes underpinning this phenomenon.

Professor Sir Mike Stratton, Senior Author and Director of the Wellcome Sanger Institute, expressed:

“Understanding why our cells age and the mechanisms behind ageing may help us find new ways to protect against age-related disease. This research indicates that accumulation of mutations during the course of a lifetime is unlikely, on its own, to account for the constellation of features that we term ageing. Further studies are therefore required to understand what changes occurring in cells during life cause the behaviours associated with ageing.”

Image credit: canva

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Ageing / Cancer / Mutations